Carbene Intermediates Research Articles

Generation of (amino)(boryloxy)carbenes from carbamoylboranes and their coupling reaction with aldehydes.

Carbamoylboranes were found to react with various aldehydes under heating conditions to give α-hydroxycarboxamides in good yields. A DFT study supports the mechanism, which involves thermally generated (amino)(boryloxy)carbene intermediates. To our knowledge, this is the first report on the generation of (amino)(boryloxy)carbene intermediates from carbamoylboranes and its application to carbon-carbon bond-forming reactions.

KOtBu-promoted C3-homocoupling of quinoxalinones through single electron transfer from an sp2 carbanion intermediate.

The C3-selective homodimerization of quinoxalinones is described. A C3-sp2 carbanion species generated through deprotonation of quinoxalinone using potassium tert-butoxide (KOtBu) transfers an electron (single electron transfer mechanism) to a second quinoxalinone, affording a radical-anion intermediate. The radical scavenging and electron paramagnetic resonance (EPR) experiments support the plausible radical reaction pathway. A mild reaction temperature and a short reaction time were attained under cost-effective conditions, which reveal the amenability of this protocol to pharmaceutical and chemical industries.

A copper-catalyzed three-component reaction of dithioacetals with diazo ketones and ketimines.

A copper-catalyzed three-component reaction of dithioacetals with diazo-ketones and ketimines has been reported. This reaction proceeds via trapping of the highly active sulfur ylide species, which are generated from thioacetal and carbene intermediates, with isatin-derived ketimine, providing an efficient protocol for the synthesis of acyclic thioacetal derivatives and medium-sized sulfur-containing heterocycles in good to high yields under mild reaction conditions with a broad substrate scope.

Mechanistic investigation of enolate/stabilized vinylogous carbanion-mediated organocatalytic azide (3 + 2) cycloaddition reactions for the synthesis of 1,2,3-triazoles.

Herein, we report a fully detailed mechanistic study involving an organocatalyzed 1,3-dipolar cycloaddition via enolate or stabilized vinylogous carbanion intermediates and azide for the synthesis of 1,2,3-triazoles. A detailed investigation of the elementary steps, intermediates, and transition states of the two organocatalyzed metal-free click reactions is supported by DFT calculations and 1H NMR monitoring experiments, providing detailed profiles for both reaction mechanisms. Distortion-interaction activation-strain (DIAS) analysis was also employed to further elucidate the regioselectivity in both reactions.

Photochemical synthesis of 1,2,4-triazoles via addition reaction of triplet intermediates to diazoalkanes and azomethine ylide intermediates.

The reactivity of diazoalkanes most commonly proceeds through the formation of carbene intermediates or dipolar cycloaddition reactions. The reaction of diazoalkanes with intermediates with unpaired electrons, however, is much less elaborated. Herein, we report on the photochemical reaction of acceptor-only diazoalkanes with azodicarboxylates. Photoexcitation of the latter results in the formation of a triplet species, which undergoes an addition reaction with diazoalkanes and formation of an azomethine ylide followed by dipolar cycloaddition reaction with organic nitriles to give a 1,2,4-triazole. The application of this transformation was elaborated in a broad and general substrate scope (48 examples), including scale-up via flow chemistry and downstream transformations. Experimental and computational studies were performed to elucidate the reaction mechanism and to rationalize the reaction outcome.

Modular construction of α-furanyl ketones via semi-pinacol rearrangement-mediated ring expansion

An efficient semi-pinacol rearrangement strategy of enynals involving a metal carbene intermediate has been developed, which allows the practical synthesis of various functionalized α-furanyl ketones in moderate to good yields under mild reaction conditions.

Controlling Ligand Coordination Spheres and Cluster Fusion in Superatoms.

We show that reaction pathways from a single superatom motif can be controlled through subtle electronic modification of the outer ligand spheres. Chevrel-type [Co6Se8L6] (L = PR3, CO) superatoms are used to form carbene-terminated clusters, the reactivity of which can be influenced through the electronic effects of the surrounding ligands. This carbene provides new routes for ligand substitution chemistry, which is used to selectively install cyanide or pyridine ligands which were previously inaccessible in these cobalt-based clusters. The surrounding ligands also impact the ability of this carbene to create larger fused clusters of the type [Co12Se16L10], providing underlying information for cluster fusion mechanisms. We use this information to develop methods of creating dimeric clusters with functionalized surface ligands with site specificity, putting new ligands in specific positions on this anisotropic core. Finally, adjusting the carbene intermediates can also be used to perturb the geometry of the [Co6Se8] core itself, as we demonstrate with a multicarbene adduct that displays a substantially anisotropic core. These additional levels of synthetic control could prove instrumental for using superatomic clusters for many applications including catalysis, electronic devices, and creating novel extended structures.

Access to 3-Sulfonamidoquinolines by Gold-Catalyzed Cyclization of 1-(2'-Azidoaryl)propargylsulfonamides through 1,2-N Migration.

We describe a gold-catalyzed cyclization of 1-(2'-azidoaryl)propargylsulfonamides for the synthesis of 3-sulfonamidoquinolines, featuring a rare and highly selective 1,2-N migration. The key α-imino gold carbene intermediate is generated through an intramolecular nucleophilic attack of the azide group to the Au-activated triple bonds in a 6-endo-dig manner.

Triarylborane Catalyzed Carbene Transfer Reactions Using Diazo Precursors.

Reactive carbenes generated from diazo compounds are key intermediates for a range of organic reactions to afford synthetically useful organic compounds. The majority of these reactions have been carried out using transition metal catalysts. However, the formation of carbene intermediates using main group elements has not been widely investigated for synthetic purposes. Recent studies have demonstrated that triarylboranes can be used for the in situ generation of reactive carbene intermediates in both stoichiometric and catalytic reactions. These new reactivities of triarylboranes have gained significant attention in synthetic chemistry particularly in catalytic studies. The range of organic compounds that have been synthesized through these reactions are important as pharmaceuticals or agrochemicals. In this perspective, we highlight the recent progress and ongoing challenges of carbene transfer reactions generated from their corresponding diazo precursors using triarylboranes as catalysts. We also highlight the stoichiometric use of triarylboranes in which the boranes not only activate the diazo functionality to afford a carbene intermediate but also actively participate in the reactions as a reagent. The different mechanisms for activation and carbene transfer are described along with the mechanistic and computational studies that have aided the elucidation of these reaction pathways. Potential opportunities for the use of boranes as a catalyst toward different carbene transfer reactions and their future prospects are discussed.

Understanding diversified chemoseletivities in Rh2(II)-catalyzed intramolecular annulation reactions of diazo and N-Sulfonyl-1,2,3-triazole compounds: A DFT study

Computational studies were performed to shed light on the origins of diversified chemoseletivities in Rh2(II)-catalyzed intramolecular annulation reactions of structurally analogous diazo and N-sulfonyl-1,2,3-triazole compounds. For methyl 2-diazo-5-phenylpentanoate (1) and 1-diazo-4-phenylbutan-2-one (3), after the formation of key Rh2(II)-carbenes, the intramolecular cyclization to form norcaradiene intermediates is ready to occur, which could further lead to annulated cycloheptatriene derivatives. Computational results suggest that the step of three-membered ring formation in the generation of a norcaradiene intermediate is considerably sensitive to steric hindrance. For the Rh2(II)-catalyzed intramolecular annulation reaction of ethyl 2-diazo-3-oxo-5-phenylpentanoate (5), bearing two electron-withdrawing groups, the commonly supposed electronic effect, however, may not play an important role in determining the chemoselectivity of 1,2-H migration over the formation of a norcaradiene intermediate. For the Rh2(II)-catalyzed intramolecular annulation of structurally analogous 1,2,3-triazole carbene precursor (7), due to the presence of imino group in the key Rh2(II)-azavinyl carbene intermediate, the feasible intramolecular cyclization in the Rh2(II)-carbene intermediates could be converted to an intramolecular [3+2] cycloaddition in a one-step manner.

Photocatalytic gem-Difluoroolefination Reactions by a Formal C-C Coupling/Defluorination Reaction with Diazoacetates.

The photolysis of diazoalkanes to conduct singlet carbene transfer reactions of colored diazoalkanes has recently attracted significant interest in organic synthesis. Herein, we describe a photocatalytic approach that allows the access of triplet carbene intermediates via energy transfer to conduct highly efficient gem‐difluoroolefination reactions with α‐trifluoromethyl styrenes. The use of a tertiary amines proved pivotal to unlock this unusual reaction pathway and to prevent undesired cyclopropanation pathways. The amine further facilitates the ultimate abstraction of fluoride to yield gem‐difluoroolefins (43 examples, up to 88 % yield), which is supported by experimental and theoretical mechanistic studies. We explored this synthesis method with a broad substrate scope, ranging from simple olefins and heterocyclic olefins towards the decoration of pharmaceutically relevant building blocks.

Borane Catalyzed Selective Diazo Cross‐Coupling Towards Pyrazoles

AbstractDecomposition of donor‐acceptor diazo compounds leads to the formation of reactive carbene intermediates. These can undergo a wide variety of carbene transfer reactions to yield synthetically useful products. Herein, we report a selective borane catalyzed cyclization reaction from the combination of two different diazo compounds to afford N‐substituted pyrazoles. The selective decomposition of the more reactive α‐aryl α‐diazoester and subsequent reaction with a vinyl diazoacetate produces N‐alkylated pyrazoles in a regioselective manner. Catalytic amounts of tris(pentafluorophenyl)borane (10 mol%) were employed to afford the pyrazole products (36 examples) in yields from 59 to 80%. Extensive DFT studies have been undertaken to interpret the mechanism for this reaction which was found to go through two tandem catalytic cycles, both catalyzed by B(C6F5)3.magnified image

Gold‐Catalyzed Intramolecular Tandem Cyclization of Alkynol‐Tethered Alkylidenecyclopropanes to Construct Naphthalene‐Fused Eight‐ to Eleven‐Membered Cyclic Ethers

AbstractA gold‐catalyzed intramolecular tandem cyclization of alkynol‐tethered alkylidenecyclopropanes was reported in this paper, providing a synthetic route to access naphthalene‐fused eight‐ to eleven‐membered cyclic ether derivatives in moderate to good yields. On the basis of control experiments and DFT calculations, a reasonable reaction mechanism involving a gold carbene intermediate was proposed, which was formed via the 6‐endo‐dig enyne cyclization process.magnified image

Polymer Skeletal Editing via Anionic Brook Rearrangements.

This report communicates the first example of polymer backbone metamorphosis affected by anionic 1,2-Brook rearrangement of acyl silane moieties. Introduction of the acyl silane functionality into a polymer backbone was achieved via acyclic diene metathesis copolymerization (ADMET) of diene 1 and two dienes. We demonstrate that, using organolithium species and cyanide as nucleophiles, the backbones of resulting copolymers can be triggered to undergo highly efficient 1,2-Brook rearrangement, which transforms the poly(acyl silane)s into poly(silyl ether)s. Furthermore, the carbanion intermediate of the 1,2-Brook rearrangement can be intercepted by ketone electrophiles to give rise to polymers with quaternary stereogenic centers in the backbone and pendant functionality. Such structural editing of polymer backbones enables a new retrosynthetic paradigm for silicon-containing polymers that could not be accessed by traditional means.

Gold(I)‐Catalyzed Indole Synthesis through Aza‐Nazarov‐Type Cyclization of α‐Imino Gold Carbene Complexes and Arenes

AbstractHere we report a gold(I)‐catalyzed and atom‐economical ortho‐N‐indolyl‐N‐pyrazolylbenzene synthesis from 1,2,3‐triazapentalenes and ynamides. The reaction occurs through the cleavage of the triazole ring and formation of a α‐imino gold carbene intermediate. An aza‐Nazarov‐type cyclization with participation of an arene ring is involved. The reaction consists in a formal [4+1] heterocycloaddition where the four‐carbon synthon is provided by the ynamide. Finally, indole synthesis could also be performed in a one‐pot procedure from their 1‐propargyl‐1H‐benzotrizaole precursors.magnified image

Gold-Catalyzed Nitrene Transfer from Benzofuroxans to N-Allylynamides: Synthesis of 3-Azabicyclo[3.1.0]hexanes.

The gold-catalyzed reaction between benzofuroxans, functioning as nitrene transfer reagents, and N-allylynamides leads to 3-azabicyclo[3.1.0]hexan-2-imines. This highly selective annulation proceeds smoothly under mild conditions (5 mol % Ph3PAuNTf2, PhCl, 60 °C) and exhibits high functional group tolerance (21 examples, ≤96% yields). The obtained cyclopropanated products represent a useful synthetic platform with an easily modulated substitution pattern as illustrated by their postmodifications. Intramolecular cyclopropanation of gold α-imino carbene intermediates is suggested as a key step of the catalytic cycle.

Ethyl cellulose derived porous iron@N-doped carbon material for N–H carbene insertion reaction

A newly developed, facile and sustainable strategy, in which zinc salt, melamine and ethyl cellulose are applied as pore-forming agent, nitrogen and carbon source respectively, has been disclosed for the synthesis of Fe/N-codoped carbon materials. This material exhibits excellent catalytic efficiency towards N–H carbene insertion reaction for the synthesis of unnatural amino acid derivatives. Fe/FeOx nanoparticles tranfer electrons to N-doped carbon owing to the Mott-Schottky Effect, which is beneficial to the formation of iron carbene intermediate. N-doping can offer more Lewis base sites, which promotes the proton transfer process. Fe/FeOx nanoparticles are coated with graphitic carbon, thereby avoiding the loss and deactivation of iron sites in this material. Therefore, this material can be reused at least four times without significant loss in activity.

Assembling Complex Structures through Cascade and Cycloaddition Processes via Non-Acceptor Gold or Rhodium Carbenes

AbstractThe ability of highly energetic metal–carbene intermediates to engage in complex cascade or formal cycloaddition processes is one of the most powerful tools for building intricate molecular architectures in a straightforward manner. Among this type of organometallic intermediates, non-acceptor metal carbenes are particularly challenging to access and, therefore, have experienced slower development. In this regard, our group has exploited the use of electrophilic gold(I) complexes to selectively activate certain classes of substrates for the generation of this type of intermediate. Thus, very different types of molecules, such as enynes or 7-substituted cycloheptatrienes, lead to the formation of carbenes under gold(I) catalysis. Related rhodium(II) carbenes can also be generated from cycloheptatrienes. In this account, we aim to summarize our efforts towards the in situ generation of such highly versatile organometallic species as well as studies on their reactivity through formal cycloadditions or complex cascade reactions.1 Introduction2 Generation of Au(I)-Vinylcarbenes via a Cycloisomerization/1,5-Alkoxy Migration Cascade2.1 Intramolecular Trapping of Au(I) Vinylcarbenes2.1.1 Applications in Total Synthesis2.2 Intermolecular Trapping of Au(I) Vinylcarbenes2.2.1 Total Synthesis of Schisanwilsonene A2.2.2 Trapping with Furans, 1,3-Dicarbonyl Compounds and Cyclic Alkenes2.2.3 Mechanism of the Cycloisomerization/1,5-Migration Sequence and the Role of the OR Migrating Group2.2.4 (4+3) Cycloadditions from Enynes3 Formal Cycloadditions of Simple Donor Metal Carbenes3.1 The Metal-Catalyzed Retro-Buchner Reaction3.2 Formal Cycloadditions with Non-Acceptor Carbenes via Metal-Catalyzed Aromative Decarbenations3.2.1 (4+1) Cycloadditions of Au(I) Carbenes3.2.2 (3+2) Cycloadditions of Au(I) Carbenes3.2.3 (4+3) Cycloadditions of Rh(II) Carbenes4 Concluding Remarks

Enantioselective Oxidative Multi-Functionalization of Terminal Alkynes with Nitrones and Alcohols for Expeditious Assembly of Chiral α-Alkoxy-β-amino-ketones.

Catalytic oxidative functionalization of alkynes has emerged as an effective method in synthetic chemistry in recent decades. However, enantioselective transformations via metal carbene intermediates are quite rare due to the lack of robust chiral catalysts, especially in the intermolecular versions. Herein, we report the first asymmetric three-component reaction of commercially available alkynes with nitrones and alcohols, which affords α-alkoxy-β-amino-ketones in good yields with high to excellent enantioselectivity using combined catalysis by an achiral gold complex and a chiral spiro phosphoric acid (CPA). Mechanistically, this atom-economic reaction involves a catalytic alkyne oxidation/ylide formation/Mannich-type addition sequence that uses nitrone as the oxidant and the leaving fragment imine as the electrophile, providing a novel method for multi-functionalization of commercially available terminal alkynes.

Visible-light photoredox-catalyzed selective carboxylation of C(sp3)−F bonds with CO2

Visible-light photoredox-catalyzed selective carboxylation of C(sp3)−F bonds with CO2